No treatments exist which have been proven to modify the course of scleroderma, a disease with median life expectancy of less than 10 years. Experimental evidence has implicated ischemia-reperfusion- induced injury, metal-catalyzed modifications of autoantigen structure, and excess fibroblast collagen production in the pathogenesis of this disease. Zinc has been shown in vitro to inhibit each of these processes. Zinc has been used safely for the treatment of other conditions, notably Wilson's Disease, but the safety of zinc therapy in scleroderma patients remains to be established. The aim of this study was to assess the safety and bioavailability of oral zinc sulfate in scleroderma patients. Using a dosing regimen common to Wilson's Disease therapy, patients with diffuse scleroderma were montiored clinically for adverse events as the primary study outcome over a 6-week trial. Six patients entered the study. There were no significant adverse events, and no protocol dropouts. Serum zinc levels increased from 79.6+/- 11.2ug/dl (mean +/- standard deviation) to 129.6 +/- 35.1 ug/dl, a statistically significant difference (Student's t test p=0.0163). This increase in serum zinc levels was consistent with results previously reported for normal subjects. Mean improvements in patient and physician global visual analog scale scores, health assessment questionnaire scores, and modified Rodnan skin scores were observed with zinc therapy, but did not reach statistical significance. Three of the six patients elected to continue taking zinc at the conclusion of the study protocol due to a subjective sense of benefit. The results of this study suggest that zinc therapy is safe and bioavailable in scleroderma patients. A Phase II trial to assess for clinical benefits of zinc therapy in scleroderma is warranted.